Based on excess over the requirement methionine is the most toxic amino acid. Necrosis of the liver, kidney, pancreas, spleen and increased fragility of the red blood cells are evident in young animals consuming excess methionine whereas consumption of similar levels are not damaging in the adult. Our work indicates that metabolism of the methionine methyl group is involved in the tissue damage and that at least two pathways in addition to that involved in the synthesis of phospholipid choline from methionine are important in conversion of the methyl group to CO2. The relative importance of these pathways will be assessed by using radioactive substrates, specific inhibitors, and isolation of the products. One pathway may not involve activation of methionine to S-adenosylmethionine (SAM) and is inhibited by S- methylcysteine. Studies will be carried out with S-methyl-cysteine and then methionine to unequivocally show that this pathway exists and that S-methylcysteine may be used as an analogue of methionine to study factors affecting the metabolism of methionine via this pathway. S- methylcysteine is as toxic as methionine. Tissue damage due to consumption of excessive levels of S-methylcysteine and methionine will be compared using standard histological techniques. Inhibitors of this pathway will be sought in an attempt to protect against the toxic action of methionine. The role that glycine and serine play in the adaptation to the high methionine diets will be investigated by using labeled substrates and isolation of products.